Osteopontin (OPN) is an arginine-glycine-aspartate (RGD)-containing acidic phosphoprotein implicated in bone morphogenesis, kidney function, tumor metastasis, and bacterial resistance. While expression of OPN in normal tissues appears restricted to mineralizing and several non- mineralizing tissues, we have found that OPN MRNA and protein increase dramatically in several different tissue injury scenarios including renal tubulointerstitial fibrosis, arterial intimal hyperplasia, atherosclerosis, and myocardial necrosis, implying a broad role for OPN during tissue injury and wound repair. These roles may include facilitating cell-cell or cell-substrate interactions. In specific animal models of disease, we have demonstrated by in situ hybridization and immunocytochemical techniques that OPN is specifically upregulated in tubular epithelium., smooth muscle cells and macrophages depending on the site and type of injury. This data suggests that lineage and injury- related factors probably work in a concerted fashion to regulate OPN expression in vivo. While regulation of OPN expression in bone and epidermal cells by systemically active hormones has been addressed, little is known about control of OPN expression by locally-derived factors present in wounded tissue. This project seeks to understand OPN functions and expression during tissue injury, focussing on renal and vascular models, in two ways: 1) by looking at the effect of OPN on macrophage function in vitro and in vivo and 20 by delineating the basal control of OPN gene expression in renal tubular epithelial cells, macrophage, and smooth muscle cells, and its modification by locally-derived factors thought to be present in wounded tissue. These studies may help to identify possible pharmacological approaches to control OPN synthesis under situations where its presence or absence may be deleterious. An understanding of the cis-acting elements involved in local control of OPN expression might also identify an 'injury-specific' promoter which could be useful for regulating expression of therapeutic transgenes in the future.